Estimates indicate that drug abuse and addiction cost the U.S. economy nearly one half-trillion dollars per year. Addiction to cocaine is characterized by compulsive drug taking behavior, despite adverse consequences. The mechanisms driving this behavior are not well understood, but involve stress, which can trigger craving. In animal models this is attributed to an interaction between the neuropeptide corticotropin releasing factor (CRF) and glutamate in the Ventral Tegmental Area (VTA). However, there remains a lack of understanding of the cellular mechanism underlying this interaction. This hampers the development of effective pharmacological treatment strategies for drug abuse and addiction. The long-term objective of this proposal is to identify cellular abnormalities in the VTA that may provide effective therapeutic targets to restore function and thereby prevent relapse to drug seeking. In dopamine neurons, firing patterns are regulated in part by activation of metabotropic glutamate receptors (mGluRs), which mediate a firing 'pause' through activation of calcium activated potassium (sK) channels. The goal of this proposal is to demonstrate that cocaine-induced changes in neuroplasticity in VTA dopamine neurons result from a deficiency in post-synaptic glutamatergic neurotransmission. To explore the interaction between CRF and glutamate-inhibition in dopamine neurons, we will record currents mediated by mGluRs that are coupled to inhibitory sK channels. Patch-clamp recordings will be performed in acute brain slices from rats trained to self-administer cocaine and control (yoked saline) rats, before or afte yohimbine-induced reinstatement. The functional impact of and the mechanism underlying the CRF-R2/mGluR receptor interaction is unknown and will be investigated in Aim-1 and Aim-2. Aim-3 will manipulate cellular targets in vivo and validate the changes in cocaine-reinstatement and the underlying mGluR/sK channel inhibition. The hypothesis that is central to this proposal is that the CRF-R2 signaling cascade is upregulated by chronic cocaine self-administration and depresses mGluR mediated inhibition during reinstatement, and that amelioration of this cocaine-induced pathology will inhibit cocaine-seeking. The results of the proposed experiments are expected to positively influence human health because they should identify novel cellular targets for development of improved therapies to treat stress-related drug-seeking behaviors.